1. Field of the Invention
The present invention relates to polyamine biosynthesis inhibitors. More particularly, the present invention relates to derivatives of S-adenosyl-(1,8-diamino-3-thiooctane) as polyamine biosynthesis inhibitors.
2. Description of the Prior Art
The synthesis of such polyamines as putrescine, spermidine and spermine in biological systems is of considerable importance in cellular replication, as evidenced by the multitude of stimuli which elicit changes in the intracellular level of the polyamines and/or their biosynthetic enzymes. In biological systems the polyamines are synthesized by a pair of aminopropyltransferases (APT), which are spermidine synthase and spermine synthase. In these reactions, nucleophilic attack by either putrescine or spermidine at an electrophilic methylene carbon atom of decarboxylated S-adenosylmethionine (dcSAM) results in the synthesis of the polyamine products, spermidine and spermine, respectively. (U.S. Pat. Nos. 3,954,726 and 4,028,183 describe the preparation of stable salts of S-adenosyl-L-methionine (SAM) which is the parent compound of dcSAM.) A related study in enzyme catalyzed alkylation reactions has shown that the mechanism of reactions involving the S-adenosylmethionine (SAM)-dependent methylase enzyme, catechol-O-methyltransferase (COMT), proceeds by a random, sequential mechanism which involves direct nucleophilic attack of the catechol hydroxyl group on the methyl carbon atom of S-adenosylmethionine. (R. W. Woodard et al, J. Biol. Chem., 255, 9124 (1980)) This mechanism probably involves general-base catalyzed proton abstraction. In another study non-specific inhibition of the enzymatic action of SAM-dependent methylases and aminopropyl transferases by the nucleoside products, S-adenosyl-homocysteine (SAH) and 5'-methylthioadenosine (MTA), respectively. However, a need continues to exist for specific inhibitors of alkyl transfer reactions by a molecule which embodies the structural features of proposed enzyme-bound transition states.